Salmonella enterica serotype Typhimurium (S. typhimurium) causes gastroenteritis, a diarrheal illness characterized by acute intestinal inflammation. The pathogen triggers inflammation by using its virulence factors to invade the intestinal epithelium and survive in tissue macrophages. Inflammation is accompanied by changes in the luminal environment, which tip the balance in the competition between S. typhimurium and the resident microbiota in favor of the pathogen. The question of which mechanisms are responsible for these changes in the microbiota composition represents a high-impact topic that will be addressed in this application. Our central hypothesis is that inflammation generates a new respiratory electron acceptor, tetrathionate, which promotes a luminal outgrowth of S. typhimurium by enabling the pathogen to utilize compounds that cannot be further broken down by fermentation in the anaerobic environment of the gut. We will test different aspects of our hypothesis by determining whether removal of sulfide can prevent tetrathionate respiration in the gut (Aim 1), the role of energy taxis during growth in the inflamed gut (Aim 2) and whether S. typhimurium utilizes specific nutrients during inflammation (Aim 3). The proposed research will drive knowledge about gastroenteritis to a higher level by providing critical new insights into molecular mechanisms that control the balance between the pathogen, the host and its microbiota (Aims 2 and 3) and by facilitating the development of new intervention strategies through science (Aim 1). The conceptual advances resulting from the proposed work are thus expected to have a strong and sustained influence on the field. PUBLIC HEALTH RELEVANCE: Non-typhoidal Salmonella serotypes are the single most common cause of death from diarrheal disease associated with viruses, parasites or bacteria and the leading cause of food-borne disease outbreaks in the United States, producing between $0.5 billion to $2.3 billion in annual costs for medical care and lost productivity. The most common human clinical isolates are Salmonella enterica serotypes Typhimurium (S. typhimurium) and Enteritidis (S. Enteritidis). Research proposed in this application will support pioneering studies on molecular mechanisms that control the balance between the pathogen, the host and its microbiota. The proposed studies will drive knowledge about Salmonella gastroenteritis to a higher level by providing critical new insights into pathogenesis and by facilitating the development of new intervention strategies through science.